Scientists Identify Most Lethal Known Species of Prion Protein

By Eric Sauter

Scientists
from the Florida campus of The Scripps Research Institute have identified a single
prion protein that causes neuronal death similar to that seen in “mad cow”
disease, but is at least 10 times more lethal than larger prion species.

This
toxic single molecule or “monomer” challenges the prevailing concept that neuronal damage is linked to the toxicity of prion protein
aggregates called “oligomers.”

The
study was published recently in an advance, online edition of the journal Proceedings of the National Academy of
Sciences.

“By
identifying a single molecule as the most toxic species of prion proteins,
we’ve opened a new chapter in understanding how prion-induced neurodegeneration
occurs,” said Scripps Florida Professor Corinne Lasmézas, who led the new study.
“We didn’t think we would find
neuronal death from this toxic monomer so close to what normally happens in the
disease state. Now we have a powerful tool to explore the mechanisms of
neurodegeneration.”

In
the study, the newly identified toxic form of abnormal prion protein, known as
TPrP, caused several forms of neuronal damage ranging from apoptosis (programmed
cell death) to autophagy, the self-eating of cellular components, as well as
molecular signatures remarkably similar to that observed in the brains of
prion-infected animals. The study found the most toxic form of prion protein
was a specific structure known as alpha-helical.

New Paths to Explore

In
addition to the insights it offers into prion diseases such as “mad cow” and a
rare human form Creutzfeldt-Jakob disease, the study opens the possibility that
similar neurotoxic proteins might be involved in neurodegenerative disorders
such as Alzheimer’s and Parkinson diseases.

In
prion disease, infectious prions (short for proteinaceous
infectious particles), thought to be composed solely of protein, have the
ability to reproduce, despite the fact that they lack DNA and RNA. Mammalian
cells normally produce what is known as cellular prion protein or PrP; during
infection with a prion disease, the abnormal or misfolded protein converts the
normal host prion protein into its disease form.

Lasmézas
explains that prion diseases are similar to Alzheimer's and other protein
misfolding diseases in that they are caused by the toxicity of a misfolded host
protein. Recent work, as reported in The
New York Times, also found that diseases such as Alzheimer's resemble prion
diseases by spreading from cell to cell.

The
new study adds another twist. “Until now, it was thought that oligomers of
proteins are toxic in all these diseases,” Lasmézas said. “Since we found for
the first time that an abnormally folded monomer is highly toxic, it opens up
the possibility that this might be true also for some other protein misfolding
diseases as well.”

“By identifying a single molecule as the most toxic species of prion
proteins, we’ve opened a new chapter in understanding how prion-induced
neurodegeneration occurs,” says Professor Corinne Lasmézas. (Photo by Randy Smith.)